above for 3a , first to elute was ketone 4b as a white solid (14.5
mg, 6%): TLC Rf ) 0.45 (70% EtOAc in hexanes); mp 142-144
°C; [R]20D 7.2 (c 1.0, MeOH); 1H NMR (400 MHz, CD3OD) δ 2.09
(s, 3 H), 3.61 (dd, 1 H, J ) 5.0, 11.3), 3.77 (q, 2 H, J ) 4.2, 11.3),
3.94 (t, 1 H, J ) 4.4), 7.54 (m, 2 H), 7.59 (m, 1 H), 7.86 (m, 2 H);
13C NMR (300 MHz, CD3OD) δ 28.5, 64.2, 66.0, 128.9, 131.0,
134.6, 143.0, 208.2; HRMS calcd for C10H14NO4S (MH+) 244.0643,
found 244.0634. Second to elute was diol 3b as an oil (210 mg,
48 h at rt when TLC (EtOAc) showed complete disappearance
of the starting acid 1. The solvent was evaporated, and the solid
residue was resuspended in CH2Cl2 (10 mL). The organic phase
was washed with an aqueous saturated solution of NaHCO3
(2 × 3 mL), 1 N NaH2PO4 (2 × 3 mL), and brine (3 mL), dried,
filtered, and evaporated to give a residue that was directly
examined by 400 MHz 1H NMR spectroscopy in CDCl3. Observa-
tion of the crude 5a and 5b and respective measurement of the
diasterotopic R-protons at 3.83 and 3.89 ppm for 5a and the
γ-protons at 0.94 and 1.03 ppm for 5b demonstrated that they
were of >97% and >98% diastereomeric purity, respectively.
(R,S)-â-Hyd r oxy-N-(Boc)va lin ylp h en yla la n in e m et h yl
ester (R,S)-5a : 1H NMR δ 1.03 (s, 3 H), 1.07 (s, 3 H), 1.35 (s, 9
H), 2.96 (dd, 1 H, J ) 5.9, 13.9), 3.09 (dd, 1 H, J ) 5.3, 14), 3.64
(s, 3 H), 3.83 (d, 1 H, J ) 9), 4.78 (m, 1 H), 5.38 (br d, 1 H, J )
8.9), 6.92 (br d, 1 H, J ) 8), 7.23-7.5 (m, 5 H).
81%): TLC Rf ) 0.40 (70% EtOAc in hexanes); [R]20 -28.1 (c
D
1.0, MeOH); 1H NMR (400 MHz, CD3OD) δ 1.10 (s, 3 H), 1.18
(s, 3 H), 3.17 (t, 1 H, J ) 5.1), 3.52 (m, 2 H), 7.53 (m, 2 H), 7.57
(m, 1 H), 7.9 (m, 2 H); 13C NMR (300 MHz, CD3OD) δ 27.0, 29.1,
63.6, 64.2, 74.7, 128.0, 131.1, 134.3, 144.2; HRMS calcd for
C11H18NO4S (MH+) 260.0957, found 260.0957. Anal. Calcd for
C
11H17NO4S: C, 50.95; H, 6.61; N, 5.40. Found: C, 50.44; H,
6.89; N, 5.24. On a larger scale, 2b (3.0 g, 12.1 mmol) gave 3b
(2.55 g, 81%) and 4b (70 mg, 2.5%).
(R,R)-â-Hyd r oxy-N-(Boc)va lin ylp h en yla la n in e m eth yl
ester (R,R)-5a : 1H NMR δ 1.08 (s, 3 H), 1.19 (s, 3 H), 1.38 (s, 9
H), 3.04 (m, 2 H), 3.66 (s, 3 H), 3.89 (d, 1 H, J ) 9), 4.79 (dd, 1
H, J ) 6.6, 13.6), 5.41 (br d, 1 H, J ) 8.9), 6.77 (br d, 1 H, J )
7.9), 7.0-7.26 (m, 5 H).
(R)-â-Hyd r oxy-N-(Boc)va lin e (1a ). A mixture of diol 3a
(439 mg, 2 mmol), sodium phosphate buffer (7.5 mL, 0.67 M,
pH ) 6.7), and TEMPO (10 mol %, 0.2 mmol, 31 mg) in MeCN
(10 mL) was heated to 35 °C and treated dropwise simulta-
neously over 2 h (Caution! Do not mix bleach and sodium chlorite
before adding to the reaction mixture)16 with sodium chlorite
(NaClO2, 200 mol %, 4 mmol, 2 mL of solution: 5.71 g 80% w/w,
50.5 mmol in 25 mL in water) and diluted bleach (NaOCl, 2 mol
%, 0.04 mmol, 1050 µL of solution: 0.66 mL commercial bleach
10.8% w/w in 25 mL of water). The mixture was stirred at 35
°C overnight, cooled to rt, treated with solid citric acid (pH )
3), and extracted with EtOAc (3 × 10 mL). The organic phases
were combined and evaporated. The residue was dissolved in a
solution of saturated Na2CO3 (20 mL) and washed with EtOAc
(2 × 10 mL). The aqueous phase was acidified with H3PO4 1 M
(pH ) 3), saturated with NaCl, and extracted with EtOAc (3 ×
20 mL). The organic phases were combined, dried, filtered, and
evaporated to give a white solid 1a (444 mg, 96%): mp 125-
(R,S)-â-Hyd r oxy-N-(ben zen esu lfon yl)va lin ylp h en yla la -
1
n in e m eth yl ester (R,S)-5b: H NMR δ 1.03 (s, 3 H), 1.28 (s,
3 H), 2.90 (m, 2 H), 3.06 (m, 1 H), 3.67 (s, 3 H), 4.59 (m, 1 H),
6.7-7.8 (m, 10 H).
(R,R)-â-Hyd r oxy-N-(ben zen esu lfon yl)va lin ylp h en yla la -
1
n in e Meth yl Ester (R,R)-5b: H NMR δ 0.94 (s, 3 H), 1.25 (s,
3 H), 2.8-3.1 (m, 3 H), 3.68 (s, 3 H), 4.62 (dd, 1 H, J ) 7.2,
13.6), 6.8-7.8 (m, 10 H).
(S)-â-Hyd r oxy-N-(Boc)va lin e. A flame-dried, 1 L, three-
necked, round-bottomed flask equipped with an overhead stirrer,
thermometer, and glass stopper, under a nitrogen atmosphere,
was charged with a solution of commercial N-Boc-D-serine
methyl ester 2a (9.0 g, 41.05 mmol) in Et2O (425 mL), cooled to
-78 °C, and treated dropwise with a 3.0 M solution of CH3MgBr
in Et2O (3.0 M, 600 mol %, 246.3 mmol, 82 mL). The dry ice
bath was removed, and the mixture was allowed to reach rt,
stirred for 1 h, cooled to 0 °C, and treated dropwise with a
solution of aqueous saturated NH4Cl (400 mL). The phases were
separated, and the aqueous layer was extracted with EtOAc
(3 × 400 mL). The organic phases were combined, washed with
brine, dried with anhydrous magnesium sulfate, filtered, and
evaporated on a rotary evaporator with a bath at 40 °C to a white
solid residue (8.37 g, 38.17 mmol) that was dissolved in MeCN
(190 mL) and treated with sodium phosphate buffer (145 mL,
0.67 M, pH ) 6.7) and TEMPO (10 mol %, 3.82 mmol, 597 mg),
heated to 35 °C, and treated dropwise simultaneously over 2 h
(Caution! Do not mix bleach and sodium chlorite before being
added to the reaction mixture) with sodium chlorite (NaClO2,
200 mol %, 76.34 mmol; 38 mL of solution: 22.84 g 80%, 202
mmol in 100 mL in water) and diluted bleach (NaOCl, 0.02 eq,
0.04 mmol, 1050 µL of solution: 2.64 mL commercial bleach
10.8% in 100 mL of water).18 The mixture was stirred at 35 °C
overnight, cooled to rt, and treated with solid citric acid (pH )
3), saturated with solid NaCl, and extracted with EtOAc (3 ×
500 mL). The organic phases were combined and evaporated.
The residue was dissolved in a solution of Na2CO3 2M (400 mL)
and washed with EtOAc (2 × 100 mL). The aqueous phase was
acidified with H3PO4 1M (pH ) 3), saturated with NaCl, and
extracted with EtOAc (3 × 200 mL). The organic phases were
combined, dried, filtered, and evaporated to give a white solid
(8.37 g). Recrystallization from a mixture of hexanes and EtOAc
gave (S)-â-hydroxy-N-(Boc)valine as white crystals (7.43 g,
126 °C; [R]20 +2.5 (c 1.0, MeOH); 1H NMR (400 MHz, CD3OD)
D
δ 1.25 (s, 3 H), 1.29 (s, 3 H), 1.45 (s, 9 H), 4.08 (s, 1 H); 13C NMR
(300 MHz, CD3OD) δ 27.8, 27.9, 29.5, 64.1, 73.2, 81.6, 158.8,
175.1; HRMS calcd for C10H20NO5 (MH+) 234.1341, found
234.1337. Anal. Calcd for C10H19NO5: C, 51.49; H, 8.21; N, 6.00.
Found: C, 51.65; H, 9.00; N, 5.97.
(R)-â-Hyd r oxy-N-(ben zen esu lfon yl)va lin e (1b). The pro-
tocol described above for 1a was employed with 3b (130 mg, 0.5
mmol) and gave a white solid 1b (127.5 mg, 93%). Alternatively,
a solution of diol 3b (134 mg, 0.512 mmol) in water (13 mL),
EtOAc (4 mL), and i-PrOH (5 mL) was treated with freshly
prepared PtO2 (50 wt %, 67 mg, from reduction at 3 atm of H2
in 8 mL of water).19 Oxygen was bubbled through the suspension
at 60 °C until all of the starting material had been consumed,
usually 24 h. The reaction mixture was cooled to rt, and the
catalyst was removed by filtration on Celite. The filtrate was
saturated with NaCl and extracted with EtOAc (3 × 20 mL).
The organic phases were combined, dried, filtered, and evapo-
rated to give a white solid 1b (106 mg, 76%): mp 164.4-165.5
1
°C; [R]20 -30.9 (c 1.0, MeOH); H NMR (400 MHz, CD3OD) δ
D
1.22 (s, 3 H), 1.26 (s, 3 H), 3.72 (s, 1 H), 7.52 (m, 2 H), 7.57 (m,
1 H), 7.84 (m, 2 H); 13C NMR (300 MHz, CD3OD) δ 27.1, 28.2,
66.4, 73.3, 129.2, 130.9, 134.6, 142.7, 173.8; HRMS calcd for
C11H16NO5S (MH+) 274.0758, found 274.0749. Anal. Calcd for
C
11H15NO4S: C, 48.20; H, 5.52; N, 5.11; S, 11.70. Found: C,
48.40; H, 5.60; N, 5.10; S, 11.92.
E n a n t iom er ic P u r it y of (R)-â-H yd r oxy-N-(Boc)va lin e
(1a ) a n d (R)-â-Hyd r oxy-N-(ben zen esu lfon yl)va lin e (1b). A
solution of (R)-â-hydroxy-N-(Boc)valine 1a (27 mg, 0.12 mmol)
or (R)-â-hydroxy-N-(benzenesulfonyl)valine 1b (32 mg, 0.12
mmol) in CH3CN (1 mL) at 0 °C was treated with HOBt (100
mol %, 22 mg, 0.12 mmol) and TBTU (150 mol %, 58 mg, 0.18
mmol) and stirred for 30 min at 0 °C. The reaction mixture was
treated with a premixed solution of (R)- or (S)-phenylalanine
methyl ester hydrochloride (300 mol %, 78 mg, 0.36 mmol) and
diisoprolyethylamine (DIEA) (400 mol %, 0.48 mmol, 62 mg, 84
µL) in CH3CN (1 mL) at 0 °C. The reaction mixture was stirred
78%): mp 125-126 °C; [R]20 -2.5 (c 1.0, MeOH).
D
Ack n ow led gm en t. This research was supported in
part by the Natural Sciences and Engineering Research
Council (NSERC) of Canada and the Ministe`re de
l’EÄ ducation du Que´bec.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of 1 and 3-5. This material is available free of charge
(19) Heyns, K.; Blazejewicz, L. Tetrahedron 1960, 9, 67.
J O026260B
J . Org. Chem, Vol. 68, No. 1, 2003 179